Essential role for zinc-triggered p75NTR activation in preconditioning neuroprotection.
Ischemic preconditioning (PC) of the brain is a phenomenon by which mild ischemic insults render neurons resistant to subsequent strong insults. Key steps in ischemic PC of the brain include caspase-3 activation and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, but upstream events have not been clearly elucidated. We have tested whether endogenous zinc is required for ischemic PC of the brain in rats. Mild, transient zinc accumulation was observed in certain neurons after ischemic PC. Moreover, intraventricular administration of CaEDTA during ischemic PC abrogated both zinc accumulation and the protective effect against subsequent full ischemia. To elucidate the mechanism of the zinc-triggered PC (Zn PC) effect, cortical cultures were exposed to sublethal levels of zinc, and 18 h later to lethal levels of zinc or NMDA. Zn PC exhibited the characteristic features of ischemic PC, including caspase-3 activation, PARP-1 cleavage, and HSP70 induction, all of which are crucial for subsequent neuroprotection against NMDA or zinc toxicity. HSP70 induction was necessary for protection, as it halted caspase-3 activation before apoptosis. Interestingly, in both Zn PC in vitro and ischemic PC in vivo, p75(NTR) was necessary for neuroprotection. These results suggest that caspase-3 activation during ischemic PC, a necessary event for subsequent neuroprotection, may result from mild zinc accumulation and the consequent p75(NTR) activation in neurons.
Lee
Jin-Yeon
JY
Department of Molecular Biology, Sejong University, Seoul 143-747, South Korea.
Kim
Yu-Jin
YJ
Kim
Tae-Youn
TY
Koh
Jae-Young
JY
Kim
Yang-Hee
YH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D018929:Cell Culture Techniques; D002540:Cerebral Cortex; D002544:Cerebral Infarction / Q000209:etiology* / Q000517:prevention & control*; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004492:Edetic Acid / Q000494:pharmacology; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D019194:Ischemic Preconditioning / Q000379:methods*; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
D002614:Chelating Agents; D018690:Excitatory Amino Acid Agonists; D020800:Receptor, Nerve Growth Factor; D016202:N-Methylaspartate; D004492:Edetic Acid; D011065:Poly(ADP-ribose) Polymerases; D015032:Zinc; D002118:Calcium